Phase I trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer

Raf-1 is a serine/threonine kinase that functions as a critical effector of Ras-mediated signal transduction via the mitogen-activated protein kinase pathway, Constitutive activation of this pathway directly contributes to ma lignant transformation in many human tumors. A 20-base phosphorothioate oli gonucleotide complementary to c-mf-1 mRNA (ISIS 5132; CGP 69846A) has been shown to specifically suppress Raf-1 expression both in vitro and in vivo. This Phase I trial, involving 22 patients with advanced cancer, was designe d to evaluate the safety, feasibility, and maximum tolerated dose of ISIS 5 132 administration as a weekly 24-h i.v. infusion, Pharmacokinetic analysis was performed, and c-raf-1 mRNA levels in peripheral blood mononuclear cel ls were assessed using quantitative reverse transcription-PCR, This trial d efined a maximum tolerated dose of 24 mg/kg/week on this schedule. Two of f our patients treated at 30 mg/kg/week had serious adverse events after the first dose of ISIS 5132, including acute hemolytic anemia and acute renal f ailure and anasarca, There were no major responses documented. Dose-depende nt complement activation was demonstrated on this schedule, but not on prev iously evaluated schedules, of ISIS 5132 administration, In contrast to oth er trials of ISIS 5132, there appeared to be no consistent suppression of p eripheral blood mononuclear cell c-raf-1 mRNA level on this schedule at any of the dose levels analyzed, These data suggest that the efficacy and toxi city profiles of antisense oligonucleotides may be highly dependent on the schedule of administration and support the analysis of the putative molecul ar target in the evaluation of novel therapeutics.